A review of bilateral sudden sensorineural hearing loss in pediatric patients.

OBJECTIVE: Bilateral, sudden sensorineural hearing loss (SSNHL) in the pediatric population is a rare phenomenon potentially detrimental to language acquisition and social development. This study comprehensively reviews and analyzes existing literature to determine any correlation or commonality in etiologies, presentations, and management of this condition. METHODS: PubMed, Cochrane, Scopus, and Web of Science databases were systematically searched for articles related to pediatric SSNHL from 1970 to 2021. Case series, case reports, and cohort studies were included. Data on patient demographics, etiology, diagnostic testing, management, and hearing recovery were collected. RESULTS: Excluding duplicates, 553 unique titles were identified by established search criteria, of which 342 titles were relevant to pediatric sudden hearing loss. Forty-six papers reported cases of bilateral SSNHL, totaling 145 individual cases. Not included in the analysis were 45 cases documented as non-organic hearing loss. The average age of the total 145 included patients was 8.5 years and 51 were male. Reported etiologies included cytomegalovirus (n = 3), meningitis (n = 13), mumps (n = 5), ototoxin exposure (n = 13), and enlarged vestibular aqueduct (n = 9). Tinnitus (n = 30) was the most reported concurrent symptom, followed by vertigo (n = 21). Systemic steroid therapy was the most common treatment and, when follow up was reported, most patients (51.2%) had complete or partial recovery of hearing. CONCLUSIONS: This is a comprehensive review of pediatric bilateral SSNHL. Though often idiopathic, etiologies also include infectious, structural, and autoimmune. Treatment largely consists of systemic steroid therapy, with variables rates of recovery. Further studies on intratympanic administration of steroids may guide future treatment.

Cervical Augmentation with an Injectable Silk-Based Gel: Biocompatibility in a Rat Model of Pregnancy.

The aim of this study was to study the biocompatibility of an injectable silk gel in the cervix in a rat model of pregnancy. The rationale is to study an injectable gel as an alternate treatment for cervical insufficiency. We further aimed to perform cervical injections via a vaginal route to mimic the clinical procedure of a cervical cerclage. We performed an in vivo study in pregnant female Sprague Dawley rats. Cervical procedures were performed using a customized speculum under general anesthesia. Injections were performed on gestational day 16. The responses to silk gel injections were compared to polyethylene terephthalate suture and saline controls on gestational day 19 and postpartum. The inflammatory response was evaluated by histology, PCR for inflammatory gene expression, and ELISA for protein levels of proinflammatory mediators. Silk gel injections were performed on 13 animals. All animals tolerated the procedure. Silk gel occupied 5% of the stroma after injection. Injected silk gel caused neither preterm birth nor prolonged pregnancy and had no effect on the kits. When comparing inflammatory responses, expression of inflammatory genes and proinflammatory proteins in the silk gel group was intermediate between saline (lowest) and cerclage suture (highest). Injectable silk gel was more inflammatory compared to saline injections but less inflammatory compared to the suture material used for cervical cerclage. This study is an important step toward development of an alternative treatment for cervical insufficiency.

Characterization of silk-hyaluronic acid composite hydrogels towards vitreous humor substitutes.

Multiple ophthalmic pathologies, such as retinal detachment and diabetic retinopathy, require the removal and replacement of the vitreous humor. Clinical tamponades such as silicone oil and fluorinated gases are utilized but limited due to complications and toxicity. Therefore, there is a need for biocompatible, stable, vitreous humor substitutes. In this study, enzymatically crosslinked silk-hyaluronic acid (HA) hydrogels formed using horseradish peroxidase and H2O2 were characterized for use as vitreous humor substitutes. The composite network structure was characterized with dynamic light scattering. In addition, the rheological, optical, and swelling properties of hydrogels with varying silk to HA ratios and crosslinking densities controlled via H2O2 were determined over time. Hydrogels had refractive indexes of 1.336 and were clear with 75-91% light transmission. Hydrogel shear storage modulus ranged between ~6 and 240 Pa where increased H2O2 increased the modulus. After 1 month of aging, there were no changes in modulus for hydrogels with lower silk ratios, while those with higher silk ratios exhibited a significant increase in modulus. Decreasing H2O2 concentration in the reactions led to increased hydrogel volume during swelling, with higher silk ratios returning to their original size after 15 days. Dynamic light scattering results show three diffusive modes, revealing the possible structures of the hydrogel composite and are consistent with the mechanical properties and swelling results. The normalized intraocular pressure of ex vivo porcine eyes after injecting hydrogels were comparable with those treated with silicone oil showing the potential clinical utility of the hydrogels as vitreous substitutes. The versatility of the silk-HA hydrogel system, the tunable swelling properties, and the stability of hydrogels with lower silk ratios show the benefit of utilizing silk-HA hydrogels as vitreous substitutes.

Ex vivo pregnant-like tissue model to assess injectable hydrogel for preterm birth prevention.

Cervical insufficiency (CI) is an important cause of preterm birth, which leads to severe newborn complications. Standard treatment for CI is cerclage, which has variable success rates, resulting in a clinical need for alternative treatments. Our objective was to develop an ex vivo model of softened cervical tissue to study an injectable silk-based hydrogel as a novel alternative treatment for CI. Cervical tissue from nonpregnant women was enzymatically treated and characterized to determine tissue hydration, collagen organization, and mechanical properties via unconfined compression. Enzymatic treatment led to an 86 ± 7.9% decrease in modulus, which correlated to a decrease in collagen organization as observed by differences in collagen birefringence. The softened tissue was injected with a crosslinked silk-hyaluronic acid composite hydrogel. After injection, the mechanical properties and volume increase of the hydrogel-treated tissue were measured resulting in a 54 ± 16% volume increase with minimal effect on tissue mechanical properties. In addition, cervical fibroblasts on silk-hyaluronic acid hydrogels remained viable and exhibited increased proliferation and metabolic activity over 5 days. Overall, this study developed an ex vivo pregnant-like human tissue model to assess cervical augmentation and showed the potential of silk-based hydrogels as an alternative treatment for cervical insufficiency.

Injectable Silk-Based Hydrogel as an Alternative to Cervical Cerclage: A Rabbit Study.

Background: Preterm birth is a common cause of morbidity and mortality in newborn infants. Cervical insufficiency (CI) is a significant cause of preterm birth. The treatment for CI is cerclage, which is a suture placed around the cervix to provide mechanical support. Cerclage, however, is associated with limited efficacy. Here we present an injectable, silk-based hydrogel as an alternative to cerclage. Objective: Pregnant rabbits were used as an animal model of pregnancy to study the mechanical properties, biocompatibility, and degradation of the hydrogel after cervical injection. Study Design: Silk hydrogel (200 µL volume) was injected into the cervix. Controls were either injected with saline or treated with cerclage (5-0 polyethylene terephthalate suture). To study the effect on mechanical properties, the cervix was tested in compression. Biodegradation of the hydrogel was followed over 6 weeks. For biocompatibility, expression levels of proinflammatory mediators were studied. Results: Hydrogel injection resulted in significant tissue augmentation-the cross-sectional area of the cervix increased 46.3 ± 3.0%. The modulus of the uninjected and hydrogel-injected tissues was 3.3 ± 0.7 and 3.2 ± 0.5 kPa at 5-10% strain, respectively (p = 0.8). Histology showed a mild inflammatory response surrounding the hydrogel. Biodegradation of the hydrogel showed 70% volume loss over 6 weeks. Hydrogel-injected tissue showed similar inflammatory response compared with cerclage. Conclusions: In pregnant rabbits, cervical injection of the silk-based hydrogel was biocompatible and naturally degraded. No adverse effects on timing of delivery and pup viability were seen. Silk-based hydrogels show promise for tissue augmentation during pregnancy. Impact Statement This research describes the use of injectable silk-based hydrogel for augmenting cervical tissue in vivo in a pregnant rabbit model. Further preclinical development of the methods and insights described in this article can lead to therapeutic use of this hydrogel as an alternative to cerclage in preterm birth due to cervical insufficiency.

3D extracellular matrix microenvironment in bioengineered tissue models of primary pediatric and adult brain tumors.

Dynamic alterations in the unique brain extracellular matrix (ECM) are involved in malignant brain tumors. Yet studies of brain ECM roles in tumor cell behavior have been difficult due to lack of access to the human brain. We present a tunable 3D bioengineered brain tissue platform by integrating microenvironmental cues of native brain-derived ECMs and live imaging to systematically evaluate patient-derived brain tumor responses. Using pediatric ependymoma and adult glioblastoma as examples, the 3D brain ECM-containing microenvironment with a balance of cell-cell and cell-matrix interactions supports distinctive phenotypes associated with tumor type-specific and ECM-dependent patterns in the tumor cells' transcriptomic and release profiles. Label-free metabolic imaging of the composite model structure identifies metabolically distinct sub-populations within a tumor type and captures extracellular lipid-containing droplets with potential implications in drug response. The versatile bioengineered 3D tumor tissue system sets the stage for mechanistic studies deciphering microenvironmental role in brain tumor progression.

Silk Hydrogels Crosslinked by the Fenton Reaction.

Here, the Fenton reaction is used to prepare silk hydrogels through oxidation of tyrosine residues in silk fibroin, leading to dityrosine crosslinking. At pH 5.7, gelation occurs rapidly within 30 s, and the resultant opaque gels show soft properties with a storage modulus of ≈100 Pa. The addition of ascorbic acid to the Fenton reaction increases the dityrosine bonds in the hydrogels but has little effect on the rheological or mechanical properties. The results indicate that Fe(III) ions significantly interacted with silk fibroin during the Fenton reaction, most likely binding to sites such as tyrosine, glutamate, and aspartate residues, triggering the formation of ß-sheet structures that may impede dityrosine bond formation due to steric hindrance. The use of an iron chelator or the operation of the Fenton reaction at pH 9.2 enables control over the interaction of Fe(III) ions with silk fibroin, achieving a hydrogel with improved optical properties and enhanced dityrosine bond formation. Hydrogels prepared by the Fenton reaction are cytocompatible as L929 mouse fibroblasts remain viable and are proliferative when seeded on the hydrogels. The results offer a useful approach to generate chemically crosslinked silk fibroin hydrogels without the use of enzyme-catalyzed reactions for biomedical applications.

Silk Molecular Weight Influences the Kinetics of Enzymatically Cross-linked Silk Hydrogel Formation.

We transform reconstituted silk solutions into robust hydrogels through covalent dityrosine cross-linking resulting from an enzymatic reaction. The bulk rheological properties and the covalent dityrosine bond formation of these gels are measured during polymerization. We compare the time-resolved bond formation to the mechanical properties, where we find that the gelation process is consistent with a model of percolation. The molecular weight of the protein determines whether a secondary mode of growth postpercolation exists, indicating that molecular weight changes affect the mechanisms by which these gels polymerize.

Enzymatically crosslinked silk-hyaluronic acid hydrogels.

In this study, silk fibroin and hyaluronic acid (HA) were enzymatically crosslinked to form biocompatible composite hydrogels with tunable mechanical properties similar to that of native tissues. The formation of di-tyrosine crosslinks between silk fibroin proteins via horseradish peroxidase has resulted in a highly elastic hydrogel but exhibits time-dependent stiffening related to silk self-assembly and crystallization. Utilizing the same method of crosslinking, tyramine-substituted HA forms hydrophilic and bioactive hydrogels that tend to have limited mechanics and degrade rapidly. To address the limitations of these singular component scaffolds, HA was covalently crosslinked with silk, forming a composite hydrogel that exhibited both mechanical integrity and hydrophilicity. The composite hydrogels were assessed using unconfined compression and infrared spectroscopy to reveal of the physical properties over time in relation to polymer concentration. In addition, the hydrogels were characterized by enzymatic degradation and for cytotoxicity. Results showed that increasing HA concentration, decreased gelation time, increased degradation rate, and reduced changes that were observed over time in mechanics, water retention, and crystallization. These hydrogel composites provide a biologically relevant system with controllable temporal stiffening and elasticity, thus offering enhanced tunable scaffolds for short or long term applications in tissue engineering.

Silk-ionomer and silk-tropoelastin hydrogels as charged three-dimensional culture platforms for the regulation of hMSC response.

The response of human bone marrow-derived mesenchymal stem cells (hMSCs) encapsulated in three-dimensional (3D) charged protein hydrogels was studied. Combining silk fibroin (S) with recombinant human tropoelastin (E) or silk ionomers (I) provided protein composite alloys with tunable physicochemical and biological features for regulating the bioactivity of encapsulated hMSCs. The effects of the biomaterial charges on hMSC viability, proliferation and chondrogenic or osteogenic differentiation were assessed. The silk-tropoelastin or silk-ionomers hydrogels supported hMSC viability, proliferation and differentiation. Gene expression of markers for chondrogenesis and osteogenesis, as well as biochemical and histological analysis, showed that hydrogels with different S/E and S/I ratios had different effects on cell fate. The negatively charged hydrogels upregulated hMSC chondrogenesis or osteogenesis, with or without specific differentiation media, and hydrogels with higher tropoelastin content inhibited the differentiation potential even in the presence of the differentiation media. The results provide insight on charge-tunable features of protein-based biomaterials to control hMSC differentiation in 3D hydrogels, as well as providing a new set of hydrogels for the compatible encapsulation and utility for cell functions. Copyright © 2016 John Wiley & Sons, Ltd.